The Transmembrane Protein Center (TMPC) proposes to function as collaborative project within the PShBiology Network. The TMPC research team has been assembled to provide diverse skills and experience in all constituent tasks of structural genomics. Our collective experience suggests that application of many techniques will be needed to expand the chances for success with the broad range of membrane proteins expected from participation in the PShBiology Network. This project is wellpoised to provide the expertise and leadership needed to successfully advance the goals of the PSLBiology Network, including outreach to new participants in this large-scale endeavor. The assembled team includes scientists with experience in the expression, production, and characterization of membrane proteins, proven ability to solve structures of complicated membrane proteins, and a strong track record of studying the interactions of membrane proteins with their protein partners and biological ligands. The team has strong grounding in the use of bioinformatics and bioanalytical techniques. Every participant brings unique experience with the function of membrane proteins, including assay development, preparation methods, or studies with either purified proteins and living organisms. This emphasis on merging the production of membrane proteins for structure determination with the power of functional characterizations is the central philosophy of our Center. The TMPC has a primary goal of determining a founding structure for each ofthe unique target classes elaborated in this proposal. Our second goal is to establish an efficient membrane protein production pipeline so that increases in throughput may be progressively obtained. The TMPC expects to improve its ability to create protein variants, to refine screening based on functional and biophysical characterizations, and to improve sorting between multiple expression pathways to find the best way produce a protein of interest. Emphasis on small-scale purification screening, and further integration of automation into our efforts will increase efficiency. Expanded options for crystallization screening, access to synchrotrons, and improvements in software used to solve structures will also contribute to the increased throughput necessary to achieve PSi:Biology goals.